Substance addiction typically follows a course of tolerance, withdrawal, compulsive drug taking behavior, drug seeking behavior, and relapse. Addictive substances include alcohol, caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other morphine-like opioid agonists such as heroin, phencyclidine and phencyclidine-like compounds, sedative ipnotics such as benzodiazepines and barbiturates and psychostimulants such as cocaine, amphetamines and amphetamine-related drugs such as dextroamphetamine and methylamphetamine. Substance abuse and addiction are public health issues. They have significant social and economic impact on both the addict and society by playing a major role in violent crime and the spread of infectious diseases. Amongst all these substance addictions, opiate-opioid addiction is the most concerned drug issues today in the U.S.
While subtle, the distinction between opioids and opiates is significant. An opiate is a drug naturally derived from the flowering opium poppy plant. Examples of opiates include heroin, morphine and codeine. On the other hand, the term opioid is a broader term that includes opiates and refers to any substance, natural or synthetic, that binds to the brain's opioid receptors—the parts of the brain responsible for controlling pain, reward and addictive behaviors. Some examples of synthetic opioids include the prescription painkillers hydrocodone (Vicodin) and oxycodone (OxyContin), as well as fentanyl and methadone. While opioid/opiate medications are prescribed to treat pain and sometimes for other health problems such as severe coughing, these drugs also affect the brain to increase pleasant feeling. Often the case these prescription opioid/opiate drugs would be misused and even abused by the people who want to pursue such pleasant feeling. Addiction is not likely to develop in a person using medication properly under a doctor's care. Addiction usually through misuse and/or abuse.
According to the World Health Organization, an estimated 13 million people abuse opiates worldwide, including 9 million heroin addicts. More than 25% of opiate abusers die from suicide, homicide, or an infectious disease, such as HIV and hepatitis, within 10-20 years of becoming addicted. Tolerance and physical dependence can develop within two to three days.
The goals for treatment of opiate/opioid addiction, as with other types of substance addictions, are to discontinue the use of the opiate/opioid while minimizing painful withdrawal symptoms and preventing relapse. Current treatments involve replacing the addictive drug with a substitution of an opioid/opiate receptor agonist or mixed agonist/antagonist. An alternative approach consists of the use of an opioid receptor antagonist to block the effect of the agonist.
An agonist is a drug that activates certain receptors in the brain. Full agonist opioids/opiates activate the opioid receptors in the brain fully resulting in the full opioid/opiate effect. Example of full agonists are heroin, fentanyl, methadone, morphine, oxycodone, hydrocodone, opium and the like.
An antagonist is a drug that blocks opioids by attaching to the opioid receptors without activating them. Antagonists cause no opioid/opiate effect and block full agonist opioids/opiates. Examples are naltrexone and naloxone. By blocking the effects of agonist opiates, opiate antagonists also prevent the development of physical dependence and tolerance to opiate drug, such as heroin.
There are partial agonists which cause less conformational change and receptor activation than full agonists. At low doses, both full and partial agonist may provide similar effects to their full agonist cousins. However, when the dose of partial agonists increases, the analgesic activity will plateau, and further increases in doses will not provide additional relief but may increase the adverse effects. Examples of partial agonists include buprenorphine, butorphanol and tramadol.
There are mixed agonists/antagonists, which demonstrate varying activity depending on the opioid receptor but also varying on the dose. Examples include buprenorphine, butorphanol, nalbuphine, and pentazocine. And, some opioids are agonists at 1 or more opioid receptors but also antagonist at other opioid receptors.
One preferred antagonist used in the treatment of former heroin addicts is naltrexone (N-cyclopropylmethylnoroxy morphone). Naltrexone therapy provides for the efficient blockade of opioid receptors and is a valuable tool in treating opiate addiction in addition to behavioral therapy and other approaches. Naltrexone, such as some opiate antagonists, provides no euphoric effects and there are no observable pharmacological consequences when a patient stops taking the drug. For naltrexone treatment to be effective, sufficient levels of the drug must be maintained in the patient for a substantial period of time. This typically requires the patient to self-administer dosages of the drug several times a week. Despite these positive outcomes associated with oral naltrexone treatment, non-compliance with oral naltrexone formulae has been a major impediment to achieving positive clinical outcomes for a significant number of patients.
A major problem with the use of opiate antagonists, such as naltrexone, in the treatment of opiate addiction has been patient compliance. One solution for improving patient compliance and concomitant rehabilitation is the parenteral in situ sustained release drug delivery of antagonist such as naltrexone over a desirably long period of time. One of the drug proprietor, Vivitrol, has formulated an injectable suspension of naltrexone which is advertised to have extended release up to 28 days. The applicant however found out that Vivitrol can only last for 21 days.
Also, for injectable naltrexone formulation, the effect of foreign body response must be taken into consideration. The human immune response to ‘non-self’ delivery formulations and vehicles typically manifests in the form of an inflammatory response, which can increase the release rate of the pharmaceutical ingredient due to increased local blood flow and macrophage infiltration. For long-acting naltrexone, local inflammation in response to drug has been noted in multiple studies. However, this exceeds the effect of the simple presence of the formulation itself and naltrexone itself has been found to increase inflammation in animal studies. Clinically, Naltrexone-injected Vivitrol™ inflammatory reactions have been implicated in the development of eosinophilic pneumonia, as well as, severe side-reactions, including death. Due to these complications, it is best to provide control of the inflammatory reaction, in conjunction with NTX, by co-delivery of an anti-inflammatory agent.
Therefore, there is a need in the art for a composition which can reduce inflammatory complications while also extend the duration of long-acting preparations. There is also a particular need in the art for an injectable composition comprising of microparticle suspensions which can reduce inflammatory reactions during administration and is featured by in situ sustained release of the composition.